tbuckley/cabot-search huggingface dataset:
Abstract 4189: Evaluation of implantable cytokine factories in combination with checkpoint inhibitors for eradication of malignant pleural mesothelioma (MPM) tumors in mice with safe and predictable dosing in non-human primates
Authors: Amanda Nash, Samira Aghlara-Fotovat, Andrea Hernandez, Bertha Castillo, Alexander Lu, Aarthi Pugazenthi, Peter Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Hee-Jin Jang, Bryan Burt, Hyun-Sung Lee, Ravi Ghanta, Omid Veiseh
Journal: Cancer Research (2022)

Abstract Pro-inflammatory cytokines have been approved as a cancer immunotherapy for treatment of metastatic melanoma and renal carcinoma for over 30 years. However, widespread use of cytokine therapy in the clinic is limited by its short half-life in circulation and the associated toxicities that emerge as a result of high systemic exposure. To overcome these limitations, we developed a clinically translatable cytokine delivery platform, called cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers. These cells are able to produce a wide range of natural cytokines (IL2, IL7, IL10, or IL12) and allow for controlled and predictable dosing in vivo. In vivo administration of cytokine factories created a high local cytokine concentration (IP space) without substantial leakage into the systemic circulation. Local, or tumor adjacent, administration of pro-inflammatory (IL-2-based) cytokine factories caused reduction of tumor burden by 70% after only 1 week of treatment when delivered as a monotherapy to mice with malignant pleural mesothelioma (MPM). Importantly, when administered in combination with local anti-PD1 injections, these cytokine factories lead to eradication of these highly aggressive tumors in 7/7 treated mice. To validate the translatability of this platform, we evaluated the safety profile in non-human primates. Significantly, this platform produced local and systemic T cell biomarker profiles that predict efficacy without renal, liver, or general toxicity in non-human primates. Our findings demonstrate the safety and efficacy of cytokine factories in preclinical animal models and provide rationale for future clinical testing for the treatment of metastatic peritoneal cancers in humans. Citation Format: Amanda Nash, Samira Aghlara-Fotovat, Andrea Hernandez, Bertha Castillo, Alexander Lu, Aarthi Pugazenthi, Peter Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Hee-Jin Jang, Bryan Burt, Hyun-Sung Lee, Ravi Ghanta, Omid Veiseh. Evaluation of implantable cytokine factories in combination with checkpoint inhibitors for eradication of malignant pleural mesothelioma (MPM) tumors in mice with safe and predictable dosing in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4189.
Anesthetic Exposure During Childhood and Neurodevelopmental Outcomes
Authors: Charles Reighard, Shaqif Junaid, William M. Jackson, Ayesha Arif, Hannah Waddington, Andrew J. O. Whitehouse, Caleb Ing
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Clinical studies of neurodevelopmental outcomes after anesthetic exposure have evaluated a range of outcomes with mixed results. <h3>Objective</h3> To examine via meta-analyses the associations between exposure to general anesthesia and domain-specific neurodevelopmental outcomes in children. <h3>Data Sources</h3> PubMed/MEDLINE, Embase, CINAHL, Web of Science and the Cochrane Library were searched from inception to August 31, 2021. <h3>Study Selection</h3> Inclusion criteria were exposures to procedures requiring general anesthesia at younger than 18 years and evaluation of long-term neurodevelopmental function after exposure. Studies lacking unexposed controls or focused on children with major underlying comorbidities were excluded. <h3>Data Extraction and Synthesis</h3> Extracted variables included effect size; hazard, risk, or odds ratio; number of exposures; procedure type; major comorbidities; age of exposure and assessment; presence of unexposed controls; and study design. Studies were independently reviewed by 2 coders, and review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model. <h3>Main Outcomes and Measures</h3> The main outcomes were standardized mean differences (SMD) for scores in the neurodevelopmental domains of academics, behavioral problems, cognition, executive function, general development, language, motor function, nonverbal reasoning, social cognition, and hazard and risk of neurodevelopmental disorder diagnoses. <h3>Results</h3> A total of 31 studies contributed data for meta-analysis. For each of the assessed neurodevelopmental domains, the numbers of children evaluated ranged from 571 to 63 315 exposed and 802 to 311 610 unexposed. Children with any exposure (single or multiple) had significantly worse behavioral problems scores, indicating more behavioral problems (SMD, −0.10; 95% CI, −0.18 to −0.02;<i>P</i> = .02), and worse scores in academics (SMD, −0.07; 95% CI −0.12 to −0.01;<i>P</i> = .02), cognition (SMD, −0.03; 95% CI, −0.05 to 0.00;<i>P</i> = .03), executive function (SMD, −0.20; 95% CI, −0.32 to −0.09;<i>P</i> &lt; .001), general development (SMD, −0.08; 95% CI, −0.13 to −0.02;<i>P</i> = .01), language (SMD, −0.08; 95% CI, −0.14 to −0.02;<i>P</i> = .01), motor function (SMD, −0.11; 95% CI, −0.21 to −0.02;<i>P</i> = .02), and nonverbal reasoning (SMD, −0.15; 95% CI, −0.27 to −0.02;<i>P</i> = .02). Higher incidences of neurodevelopmental disorder diagnoses were also reported (hazard ratio, 1.19; 95% CI, 1.09 to 1.30;<i>P</i> &lt; .001; risk ratio, 1.81; 95% CI, 1.25 to 2.61;<i>P</i> = .002). <h3>Conclusions and Relevance</h3> These findings support the hypothesis that associations between anesthetic exposure during childhood and subsequent neurodevelopmental deficits differ based on neurodevelopmental domain.
Abstract 5815: Metabolomics in an Apc-mutant genetic background: Mechanistic insights from acute vs. chronic spinach intake
Authors: Sultan Neja, Roderick H. Dashwood
Journal: Cancer Research (2022)

Abstract There is growing interest in the crosstalk between the gut microbiome, metabolomic features, and disease pathogenesis. Colorectal cancer is a major health burden worldwide, linked in part to modifiable risk factors associated with diet and lifestyle (1). The current investigation compared long-term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wildtype animals corroborated key contributions to anticancer outcomes by spinach-derived linoleate bioactives and a butanoate metabolite linked to increased α-diversity of the gut microbiome (2). Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction observed in colon tumors from rats given long-term spinach treatment. Mechanistic studies indicated reactivation of immune-associated major histocompatibility complex genes in cell-based assays and in vivo, plus differential roles of the metabolites in targeting Wnt/β-catenin signaling (3). Clinical translation of the findings from this investigation to at-risk patients might provide valuable quality-of-life benefits by delaying surgical interventions and drug therapies with adverse side effects (4,5). References1.Xi, Y., Xu, P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 2021;14: 1011741.Chen, Y.-S. et al. Dietary spinach reshapes the gut microbiome in an Apc-mutant genetic background: mechanistic insights from integrated multi-omics. Gut Microbes 2021;13:1972756. 1.Liu, F. et al. Suppression of membranous LPR5 recycling, Wnt/β-catenin signaling, and colon carcinogenesis by 15-LOX-1 peroxidation of linoleic acid in PI3P. Cell Rep 2020;32:108049.1.Ulusan, A.M. et al. Optimization of erlotinib plus sulindac dosing regimens for intestinal cancer prevention in an Apc-mutant model of Familial Adenomatous Polyposis (FAP). Cancer Prev Res (Phila) 2021;14:325-336.1.Samadder, N.J. et al. Association of sulindac and erlotinib vs placebo with colorectal neoplasia in Familial Adenomatous Polyposis: secondary analysis of a randomized clinical trial. JAMA Oncol 2018:4:671-677. Citation Format: Sultan Neja, Roderick H. Dashwood. Metabolomics in an Apc-mutant genetic background: Mechanistic insights from acute vs. chronic spinach intake [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5815.
Abstract LB525: Discovery and characterization of ABSK111, a selective, CNS-penetrable, and broad-spectrum EGFR inhibitor targeting exon20 insertion, atypical and extracellular mutations
Authors: Cheng Dai, Juan Peng, Fei Yang, Haibing Deng, Yuan Zhao, Hongping Yu, Yaochang Xu, Zhui Chen, Shuqun Yang
Journal: Cancer Research (2022)

Abstract Epidermal growth factor receptor (EGFR) exon20 insertion mutations and atypical mutations account for about 9% and 20% of EGFR-mutated non-small cell lung cancer (NSCLC), respectively. Currently approved EGFR tyrosine kinase inhibitors (TKIs) have shown efficacy in NSCLC patients with exon20 insertion and atypical mutations, but with limited overall response and high rate of EGFR-related severe adverse events. This may be associated with the inhibition of wild-type (WT) EGFR. ABSK111 is a highly potent, selective, and CNS-penetrable EGFR inhibitor, targeting multiple EGFR and HER2 mutations, including exon20 insertion, atypical, and extracellular mutations. Here we describe the preclinical in vitro and in vivo characterization of ABSK111. ABSK111 potently inhibited the proliferation of BA/F3 cell lines harboring EGFR exon20, atypical and extracellular mutations with higher selectivity for WT EGFR than currently approved EGFR TKIs. ABSK111 also suppressed HER2 atypical and exon20 mutations. Further, ABSK111 potently blocked the phosphorylation of EGFR exon20 insertion mutations and EGFR variant III in BA/F3 cell lines, with less inhibition of WT EGFR signal than the approved TKIs. Moreover, pharmacokinetic and pharmacodynamic studies demonstrated sustained and exposure-dependent suppression of p-ERK in tumor tissue following a single oral dose of ABSK111. Finally, ABSK111 showed dose-dependent anti-tumor activity in BA/F3 tumor models with EGFR exon20 insertion mutations and EGFR variant III without significant body weight loss. Pharmacodynamic analysis of endpoint samples from efficacy study showed sustained inhibition of p-ERK, which was superior to the approved exon20 insertion inhibitor mobocertinib. Taken together, these results demonstrate the ability of ABSK111 to inhibit a broad spectrum of EGFR and HER2 mutations, including exon20 insertions, atypical and extracellular mutations, while sparing the WT form of EGFR. In addition to the application in NSCLC, the activity against EGFR extracellular mutations and the ability to penetrate into brain suggest the application of ABSK111 in glioblastoma multiforme (GBM). Citation Format: Cheng Dai, Juan Peng, Fei Yang, Haibing Deng, Yuan Zhao, Hongping Yu, Yaochang Xu, Zhui Chen, Shuqun Yang. Discovery and characterization of ABSK111, a selective, CNS-penetrable, and broad-spectrum EGFR inhibitor targeting exon20 insertion, atypical and extracellular mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB525.
Chapare Hemorrhagic Fever and Virus Detection in Rodents in Bolivia in 2019
Authors: Roxana Loayza Mafayle, Maria E. Morales-Betoulle, Carla Romero, Caitlin M. Cossaboom, Shannon Whitmer, Carlos E. Alvarez Aguilera, Cinthia Avila Ardaya, Mirian Cruz Zambrana, Andrés Dávalos Anajia, Nelly Mendoza Loayza, Ana-Maria Montaño, Fernando L. Morales Alvis, Jimmy Revollo Guzmán, Sebastián Sasías Martínez, Gricel Alarcón De La Vega, Armando Medina Ramírez, Jhemis T. Molina Gutiérrez, Alex J. Cornejo Pinto, Renata Salas Bacci, Julia Brignone, Jorge Garcia, Arletta Añez, Jairo Mendez-Rico, Kleber Luz, Ariel Segales, Karen M. Torrez Cruz, Adolfo Valdivia-Cayoja, Brian R. Amman, Mary J. Choi, Bobbie-Rae Erickson, Cynthia Goldsmith, James C. Graziano, Allison Joyce, John D. Klena, Austin Leach, Jason H. Malenfant, Stuart T. Nichol, Ketan Patel, Tara Sealy, Trevor Shoemaker, Christina F. Spiropoulou, Alison Todres, Jonathan S. Towner, Joel M. Montgomery
Journal: New England Journal of Medicine (2022)

In June 2019, the Bolivian Ministry of Health reported a cluster of cases of hemorrhagic fever that started in the municipality of Caranavi and expanded to La Paz. The cause of these cases was unknown.We obtained samples for next-generation sequencing and virus isolation. Human and rodent specimens were tested by means of virus-specific real-time quantitative reverse-transcriptase-polymerase-chain-reaction assays, next-generation sequencing, and virus isolation.Nine cases of hemorrhagic fever were identified; four of the patients with this illness died. The etiologic agent was identified as Mammarenavirus Chapare mammarenavirus, or Chapare virus (CHAPV), which causes Chapare hemorrhagic fever (CHHF). Probable nosocomial transmission among health care workers was identified. Some patients with CHHF had neurologic manifestations, and those who survived had a prolonged recovery period. CHAPV RNA was detected in a variety of human body fluids (including blood; urine; nasopharyngeal, oropharyngeal, and bronchoalveolar-lavage fluid; conjunctiva; and semen) and in specimens obtained from captured small-eared pygmy rice rats (Oligoryzomys microtis). In survivors of CHHF, viral RNA was detected up to 170 days after symptom onset; CHAPV was isolated from a semen sample obtained 86 days after symptom onset.M. Chapare mammarenavirus was identified as the etiologic agent of CHHF. Both spillover from a zoonotic reservoir and possible person-to-person transmission were identified. This virus was detected in a rodent species, O. microtis. (Funded by the Bolivian Ministry of Health and others.).
Abstract 356: Pre-clinical investigations utilizing Bcl2 inhibitors in glioblastoma
Authors: Srishti Kala, Leland Earp, Sonikpreet Aulakh
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM) is a lethal malignant cancer of the central nervous system. The multimodal management approach does not extend survival beyond 2 years. Due to diverse variability in subpopulations of patients with glioma, treatment benefits are not uniform with apoptosis evasion being a key attribute of treatment resistance in GBM. Antiapoptotic protein, Bcl-2, Bcl-xL, and Mcl-1, are frequently upregulated in acquired chemo resistant cancer cells. Here in, we investigated the anti-proliferative effects of disrupting “Bcl-2-regulated pathways” in GBM. Of note, accessibility of FDA approved Bcl-2 inhibitors with known safety profile, makes it a biologically relevant target where intra- and inter-patient heterogeneity can be overcome successfully. Western Blot (WB) analysis was performed to compare the Bcl-2 family expression in human GBM cell lines (LN229, T98G, DI321, SA21). RT-PCR data was obtained for Bcl-2 family mRNA expression profile in present GBM cell lines. IC50s were determined for afore mentioned cell lines using MTS assay for Temozolomide (TMZ, alkylating agent), Bcl-2 inhibitor ABT199, Bcl-xL inhibitor A1331852, Mcl-1 inhibitor AZD5991, and BTK inhibitor Ibrutinib. Further, synergistic activity of TMZ, ABT199, A1331852, AZD5991 and Ibrutinib in several permutations. All experiments were performed with an n of 3/5. Our data suggests upregulation of antiapoptotic Bcl-2 family proteins in GBM cells including GSCs (DI321) and patient derived cells (SA21). There was significant decrease in viability of these cells when treated with ABT199 and A-1331852 (p&amp;lt; 0.0001) as compared to TMZ as a single agent. Other combinations ABT199+AZD5991 (p&amp;lt; 0.0001), AZD5991+A-1331852 (p&amp;lt; 0.0001) and TMZ+ABT (p&amp;lt;0.0002) also shows anti-tumor activity. Alternatively, we observed increased sensitivity in TMZ-resistant GBM cells against these drugs using MTS assay. GBM is an aggressive malignancy with 100% recurrence over time. Our preclinical data suggests synergism of Bcl-2 protein inhibitors in GBM cells, both TMZ-naïve and TMZ-resistant. Our ongoing research is investigating the biological relevance of Bcl-2 in conjugation with other tumor suppressor proteins, in vitro and in vivo. Citation Format: Srishti Kala, Leland Earp, Sonikpreet Aulakh. Pre-clinical investigations utilizing Bcl2 inhibitors in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 356.
Abstract 102: IGFBP6 modulates estrogen receptor alpha phosphorylation and transcriptional activity in breast cancer cells
Authors: Francisco Javier Lariz, Kevin D. Houston
Journal: Cancer Research (2022)

Abstract Insulin-like growth factors (IGFs) are signaling proteins which bind to insulin-like growth factor 1 receptor (IGF-1R) and induce a signaling cascade to promote proliferation and survival in breast cancer cells. Insulin-Like Growth Factor Binding Protein 6 (IGFBP-6) induces apoptosis by inhibiting IGF-1R upon binding to both IGF-1 and IGF-2, however, the role of IGFBP-6 in breast cancer has not been adequately studied. While IGFBP-6 can bind to both IGF-1 and IGF-2, the binding affinity for IGF2 is 20-fold higher compared to IGF1. To determine if IGFBP-6 modulates breast cancer cells, MCF-7 and T-47D cells were stably transfected with an IGFBP-6 expression plasmid. IGFBP6 over-expression resulted in decreased proliferation rates in both cell lines when compared to empty vector controls. To identify a mechanism of decreased proliferation rates, the activation of the IGF-1R-dependent AKT and MAPK mediators was measured. Reduced phosphorylation of MAPK and AKT was observed in both cell lines over-expressing IGFBP-6 compared to empty vector controls. MAPK and AKT phosphorylate ERα at serine 118 and serine 167 respectively, therefore, ERα phosphorylation at these residues was determined in the presence of IGFBP6 expression. Reduction in phosphorylation was greater in MCF-7 cells than T-47D cells when IGFBP6 was constitutively expressed. To determine if reduced ERα phosphorylation altered expression of known targets of ERα-modulated expression, such as IGF-1R and Progesterone Receptor (PR) was measured. Unexpectedly, IGF-1R and PR protein and transcript levels were greater in IGFBP6 over-expressing cells. Studies have shown that differences in ERα phosphorylation change the recruitment of transcriptional modulators associated with ERα-mediated transcription. These results suggest that despite reducing IGF-1R-dependent cell signaling, compensatory mechanisms may be induced to enhance ERα-mediated expression. Citation Format: Francisco Javier Lariz, Kevin D. Houston. IGFBP6 modulates estrogen receptor alpha phosphorylation and transcriptional activity in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 102.
Abstract 3015: Serine starvation silences estrogen receptor signaling through histone hypoacetylation
Authors: Albert M. Li, Yang Li, Bo He, Haowen Jiang, Chao Lu, Joshua J. Gruber, Erinn B. Rankin, Jiangbin Ye
Journal: Cancer Research (2022)

Abstract Estrogen receptor (ER) plays important roles in regulating normal development and female reproductive system function. Loss of ER pathway activity is a hallmark of breast cancer progression, associated with accelerated tumor proliferation and resistance to endocrine therapy. How ER loss occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in solid tumors, downregulates estrogen receptor alpha (ERα) expression, represses transcriptional targets such as progesterone receptor (PR), and reduces sensitivity to antiestrogens, suggesting a transition of ER-positive (ER+) breast cancer cells to an ER/PR-negative (ER-/PR-) state. ER downregulation under serine starvation is accompanied by a global loss of histone acetylation. These chromatin changes are driven by metabolic reprogramming triggered by serine starvation, particularly lower glucose flux through glycolysis and the TCA cycle, leading to reduced acetyl-CoA levels and histone hypoacetylation. Supplementation with acetate or glycerol triacetate (GTA), precursors of acetyl-CoA, restores H3K27 acetylation and ERα expression under serine starvation. Therefore, a major consequence of serine starvation in breast cancer could be global chromatin changes that influence lineage-specific gene expression. Citation Format: Albert M. Li, Yang Li, Bo He, Haowen Jiang, Chao Lu, Joshua J. Gruber, Erinn B. Rankin, Jiangbin Ye. Serine starvation silences estrogen receptor signaling through histone hypoacetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3015.
Abstract LB503: Using JBrowse 2 plugins to visualize cancer genomic data
Authors: Robin Andrew Haw, Colin Diesh, Caroline Bridge, Rob Buels, Garrett Stevens, Peter Xie, Teresa Martinez, Elliot Hershberg, Junjun Zhang, Shihab Dider, Scott Cain, Lincoln Stein, Ian Holmes
Journal: Cancer Research (2022)

Abstract Genome browsers are essential tools for integrating, exploring, and visualizing data from large cancer genomics datasets. JBrowse 2 is a JavaScript genome browser with novel features for visualizing structural variants, syntenic alignments, and multiple types of genomic data. Although JBrowse 2 is available as a web-based or desktop application, the capabilities and features are not fixed and can be expanded through a comprehensive plugin system. To help address users' needs, we launched the new JBrowse 2 Plugin Store (https://jbrowse.org/jb2/plugin_store/). The overarching goals of the Plugin Store are to showcase the crucial features plugins add to JBrowse 2, to enable researchers to search for plugins they need, and for developers to highlight their plugins. The plugin system spans all aspects of the JBrowse 2 application and enables new track types (e.g. Manhattan plots, Hi-C data, ideograms), data adapters (e.g. API endpoint adapters for NCI Genomic Data Commons and the International Cancer Genome Consortium), and views (e.g. dot plots and multiple sequence alignments). Here, we present the capabilities of JBrowse 2 plugins and describe usage scenarios for cancer biologists and bioinformaticians, and software developers. Citation Format: Robin Andrew Haw, Colin Diesh, Caroline Bridge, Rob Buels, Garrett Stevens, Peter Xie, Teresa Martinez, Elliot Hershberg, Junjun Zhang, Shihab Dider, Scott Cain, Lincoln Stein, Ian Holmes. Using JBrowse 2 plugins to visualize cancer genomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB503.